BACKGROUND: Cyclic vomiting syndrome (CVS) is defined by its episodic patterning. Furthermore, CVS is associated with other episodic disorders such as migraine and epilepsy. Indeed, many of the medications that are known to be useful for prophylaxis and abortive therapy in CVS are also effective in preventing and aborting migraines and seizures. These observations strongly suggest that CVS has a neural basis, but the precise pathophysiological mechanisms that operate in CVS remain unclear. PURPOSE: This brief review describes recent neurophysiological insights and opportunities to further advance the understanding of pathophysiological neural mechanisms that are present in patients with CVS. These insights are poised to translate into the next generation of neurotherapeutic strategies for CVS using central neuromodulation. Additionally, the development of neurophysiological tests of neural excitability could be positioned to shape management decisions in future CVS care.